Skip to main content
SpringerLink
Log in

β 1- andβ 2-adrenoceptor binding and functional response in right and left atria of rat heart

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

The properties ofβ 1- andβ 2-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses toβ-adrenoceptor agonists were examined. [125I](-)-pindolol (125IPIN) bound saturably and specifically to a single class of high affinity sites in homogenates of both right and left atria. Thek 1's for association in right and left atria were 6.5×109 l/mol-min and 2.3×109 l/mol-min respectively, while thek −1's for dissociation were 0.20 min−1 and 0.17 min−1. The kinetically determinedK D's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibriumK D's determined from Scatchard analysis of saturation isotherms of specific125IPIN binding. Inhibition of125IPIN binding byβ-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition byβ 1- andβ 2-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement byβ 1-selective (practolol, atenolol and metoprolol) andβ 2-selective (ICI 118,551) antagonists gave estimates of the proportion ofβ 1- andβ 2-adrenoceptors present in rat atria. Right atria contained 67±4.2%β 2-adrenoceptors and 33±4.2%β 2-adrenoceptor, while left atria contained 67±2.8%β 1- and 33±2.8%β 2-adrenoceptors. Increases in the rate of spontaneously beating right atria and the force of electrically driven left atria caused byβ-adrenoceptor agonists were also measured. pA2 values for non-subtype selectiveβ-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated withK D values determined for specific125IPIN binding. pA2 values forβ 1- andβ 2-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the pK D values of these drugs in binding toβ 1-adrenoceptors, but not with the pK D values in binding toβ 2-adrenoceptors. Dose-response curves for stimulation of both rate and force by theβ 2-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade ofβ 1-adrenoceptors with metoprolol than by selective blockade ofβ 2-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activatingβ 1-adrenoceptors. These results suggest thatβ 1- andβ 2-adrenoceptors coexist in both left and right atria of rat heart in approximately a 2∶1 ratio, however onlyβ 1-adrenoceptors mediate the chronotropic and inotropic effects ofβ-adrenoceptor agonists.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Arunlakshana O, Schild HO (1959) Some quantitative use of drug antagonists. Br J Pharmacol 14:48–58

    Google Scholar 

  • Barnes PJ, Nadel JA, Skoogh B-E, Roberts JM (1983) Characterization of beta adrenoceptor subtypes in canine airway smooth muscle by radioligand binding and physiological responses. J Pharmacol Exp Ther 225:456–461

    Google Scholar 

  • Barnett DB, Rugg EL, Nahorski SR (1978) Direct evidence for two types of beta-adrenoceptor binding site in lung tissue. Nature 273:166–168

    Google Scholar 

  • Barovsky K, Brooker G (1980) (-)-[125I]-Iodopindolol, a new highly selective radioiodinatedβ-adrenergic receptor antagonist: Measurement ofβ-receptors on intact rat astrocytoma cells. J Cyc Nucleo Res 6:297–307

    Google Scholar 

  • Broadley KJ (1982) Cardiac adrenoceptors. J Auton Pharmacol 2:119–145

    Google Scholar 

  • Broadley KJ, Nicholson CD (1981) Dissociation constants of isoprenaline and orciprenaline and their relative efficacies on guinea-pig isolated atria determined by use of an irreversibleβ-adrenoceptor antagonist. Br J Pharmacol 72:635–643

    Google Scholar 

  • Brodde O-E, Leifert FJ, Krehl H-J (1982a) Coexistence ofβ 1- andβ 2-adrenoceptors in the rabbit heart: Quantitative analysis of the regional distribution by (-)-3H-dihydroalprenolol binding. J Cardiovasc Pharmacol 4:34–43

    Google Scholar 

  • Brodde O-E, Karad K, Zerkowski H-R, Rohm N, Reidemeister JC (1982b) Demonstration ofβ 1- andβ 2-adrenoceptors in human heart by125Iodocyanopindolol (ICYP) binding. Naunyn-Schmiedeberg's Arch Pharmacol 321:R61

    Google Scholar 

  • Brodde O-E, Karad K, Zerkowski H-R, Rohm N, Reidemeister JC (1983) Coexistence ofβ 1- andβ 2-adrenoceptors in human right atrium. Circ Res 53:752–758

    Google Scholar 

  • Bryan LJ, Cole JJ, O'Donnell SR, Wanstell JC (1981) A study designed to explore the hypothesis that beta-1 adrenoceptors are “innervated” receptors and beta-2 adrenoceptors are “hormonal” receptors. J Pharm Exp Ther 216:395–400

    Google Scholar 

  • Carlsson E, Ablad B, Brandstrom A, Carlsson B (1972) Differentiated blockade of the chronotropic effects of various adrenergic stimuli in the cat heart. Life Sci 11:953–958

    Google Scholar 

  • Carlsson E, Dahlöf C-G, Hedberg A, Persson H, Tangstrand B (1977) Differentiation of cardiac chronotropic and inotropic effects ofβ-adrenoceptor agonists. Naunyn-Schmiedeberg's Arch Pharmacol 300:101–105

    Google Scholar 

  • Carswell H, Nahorski SR (1983)β-Adrenoceptor heterogeneity in guinea-pig airways: comparison of functional and receptor labelling studies. Br J Pharmacol 79:965–971

    Google Scholar 

  • Cheng Y-C, Prusoff WH (1973) Relationship between inhibition constant (k i) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108

    Google Scholar 

  • Cohen ML, Wiley KS (1978) Beta1 and beta2 receptor mechanisms in rat jugular veins: differences between norepinephrine and isoproterenol-induced relaxation. Life Sci 23:1997–2006

    Google Scholar 

  • Copeland JG, Larson DF, Roeske WR, Russell DH, Womble JR (1982)β 2-Adrenoceptors regulate induction of myocardial ornithine decarboxylase in mice in vivo. Br J Pharmacol 75:479–483

    Google Scholar 

  • Daly MJ, Long JM, Stables R (1978) The role ofβ 1- andβ 2-adrenoceptors in the inhibition of gastric acid secretion in the dog. Br J Pharmacol 64:153–157

    Google Scholar 

  • Freyss-Beguin M, Griffaton G, Lechat P, Picken D, Quennedey MC, Rouot B, Schwartz J (1983) Comparison of the chronotropic effect and the cyclic AMP accumulation induced byβ 2-agonists in rat heart cell culture. Br J Pharmacol 78:717–723

    Google Scholar 

  • Furchgott RF, Wakade TD, Sorace RA, Stollak JS (1975) Occurrence of both beta1 and beta2 receptors in guinea pig tracheal smooth muscle, and variation of the beta1:beta2 ratio. Fed Proc 34:794

    Google Scholar 

  • Hancock AA, DeLean AL, Lefkowitz RJ (1979) Quantitative resolution of beta-adrenergic receptor subtypes by selective ligand binding: Application of computerized model fitting technique. Mol Pharmacol 16:1–9

    Google Scholar 

  • Hayes R, Howard JC, Nasmyth PA (1982) The influence of drugs on the overflow of noradrenaline and the identification of receptors in guinea-pig atria. Br J Pharmacol 76:195–200

    Google Scholar 

  • Hedberg A, Mattsson H (1981) Beta-adrenoceptor interaction of full and partial agonists in the cat heart and soleus muscle. J Pharm Exp Ther 219:798–808

    Google Scholar 

  • Hedberg A, Minneman KP, Molinoff PB (1980) Differential distribution of beta-1 and beta-2 adrenergic receptors in cat and guinea pig heart. J Pharmacol Exp Ther 212:503–508

    Google Scholar 

  • Heitz A, Schwartz J, Velly J (1983)β-Adrenoceptors of the human myocardium: Determination ofβ 1- andβ 2-subtypes by radioligand binding. Br J Pharmacol 80:711–717

    Google Scholar 

  • Hoffman BB, Lefkowitz RJ (1982) Adrenergic receptors in the heart. Ann Rev Physiol 44:475–484

    Google Scholar 

  • Homberg V, Lucas M, Rosenbaum E Vassent G, Bockaert J (1981) Presence of both bata1- and beta2-adrenergic receptors in a single cell type. Mol Pharmacol 20:463–469

    Google Scholar 

  • Johansson K-H, Persson H (1983)β 2-Adrenoceptors in guinea pig atria. J Pharm Pharmacol 35:804–807

    Google Scholar 

  • Kaumann AJ, Marano M (1982) On equilibrium dissociation constants for complexes of drug-receptor subtypes. Naunyn-Schmiedeberg's Arch Pharmacol 318:192–201

    Google Scholar 

  • Kenakin TP (1982) The Schild regression in the process of receptor classification. Can J Physiol Pharmacol 60:249–265

    Google Scholar 

  • Kenakin TP, Beek D (1980) Is prenalterol (H133/80) really a selective beta1 adrenoceptor agonist? Tissue selectivity resulting from differences in stimulus-response relationships. J Pharmacol Exp Ther 213:406–413

    Google Scholar 

  • Kenakin TP, Beek D (1984) Relative efficacy of prenalterol and pirbuterol for beta-1 adrenoceptors. Measurement of agonist affinity by alteration of receptor number. J Pharm Exp Ther 229:340–345

    Google Scholar 

  • Lands AM, Arnold A, McAuliff JP, Luduena FP, Brown TG (1967) Differentiation of receptor systems activated by sympathomimetic amines. Nature 214:597–598

    Google Scholar 

  • Lau YH, Robinson RB, Rosen MR, Bilzekian JP (1980) Subclassification ofβ-adrenergic receptors in cultured rat cardiac myoblasts and fibroblasts. Circ Res 47:41–48

    Google Scholar 

  • Minneman KP, Molinoff PB (1980) Classification and quantitation of beta adrenergic receptor subtypes. Biochem Pharmacol 29:1317–1323

    Google Scholar 

  • Minneman KP, Hegstrand LR, Molinoff PB (1979a) The pharmacological specificity of beta-1 and beta-2 adrenergic receptors in rat heart and lung in vitro. Mol Pharmacol 16:21–33

    Google Scholar 

  • Minneman KP, Hegstrand LR, Molinoff PB (1979b) Simultaneous determination of beta-1 and beta-2 adrenergic receptors in tissucs containing both receptor subtypes. Mol Pharmacol 16:34–46

    Google Scholar 

  • Minneman KP, Hedberg A, Molinoff PB (1979c) Comparison of beta-adrenergic receptor subtypes in mammalian tissues. J Pharm Exp Ther 211:502–508

    Google Scholar 

  • O'Donnel SR, Wanstall JC (1977) The use of functional antagonism to determine whetherβ-adrenoceptor agonists must have a lower efficacy than isoprenaline to be trachea-atria selective in vitro in guinea-pigs. Br J Pharmacol 60:255–262

    Google Scholar 

  • O'Donnel SR, Wanstall JC (1979a) The importance of choice of agonist in studies designed to predictβ 2:β 1 adrenoceptor selectivity of antagonists from pA2 values on guinea-pig trachea and atria. Naunyn-Schmiedeberg's Arch Pharmacol 308:183–190

    Google Scholar 

  • O'Donnell SR, Wanstall JC (1979b) pA2 values of selectiveβ-adrenoceptor antagonists on isolated atria demonstrate a species difference in theβ-adrenoceptor population mediating chronotropic responses in the cat and guinea-pig. J Pharmacol 31:686–690

    Google Scholar 

  • O'Donnell SR, Wanstall JC (1981) Demonstration of bothβ 1- andβ 2-adrenoceptors mediating relaxation of isolated ring preparations of rat pulmonary artery. Br J Pharmacol 74:547–552

    Google Scholar 

  • Rugg EL, Barnett DB, Nahorski SR (1979) Coexistence of beta1 and beta2 adrenoceptors in mammalian lung: evidence from direct binding studies. Mol Pharmacol 14:996–1005

    Google Scholar 

  • Scatchard G (1949) The attraction of proteins for small molecules and ions. Ann NY Acad Sci 51:600–672

    Google Scholar 

  • Schwartz J, Velly J (1983) Theβ-adrenoceptor of pig coronary arteries: determination ofβ 1 andβ 2 subtypes by radioligand binding. Br J Pharmacol 79:409–414

    Google Scholar 

  • Shanahan EA, Wahlquist ML, Wilmshurst EG (1979) Effects ofβ 2-adrenoceptor stimulation on cardiac metabolism in the conscious dog. Br J Pharmacol 66:229–233

    Google Scholar 

  • Stiles GL, Taylor S, Lefkowitz RJ (1983) Human cardiac beta-adrenergic receptors: subtype heterogeneity delineated by direct radioligand binding. Life Sci 33:467–473

    Google Scholar 

  • Vliestra RE, Blinks JR (1976) Heterogeneity of cardiac beta-adrenoceptors. Fed Proc 35:210

    Google Scholar 

  • Zaagsma J, Oudhof R, van der Heidjen PJC, Plantje JF (1979) Subheterogeneity ofβ-adrenoceptors in the pulmonary and the cardiac system of the guinea-pig. In: Usdin E, Kopin IJ, Barchas J (eds) Catecholamines: basis and clinical frontiers. Pergamon Press, New York, pp 435–437

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Emory University School of Medicine, 30322, Atlanta, Georgia, USA

    Eric N. Juberg, Kenneth P. Minneman & Peter W. Abel

Authors
  1. Eric N. Juberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenneth P. Minneman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter W. Abel
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported by a grant from the American Heart Association — Georgia Affiliate

Rights and permissions

Reprints and permissions

About this article

Cite this article

Juberg, E.N., Minneman, K.P. & Abel, P.W. β 1- andβ 2-adrenoceptor binding and functional response in right and left atria of rat heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 330, 193–202 (1985). https://doi.org/10.1007/BF00572434

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00572434

Key words

Search

Navigation